Composition comprising at least one oxazolin for inhibiting langerhans cell migratio, and uses thereof

ABSTRACT

The invention concerns a composition containing at least an oxazolin, optionally combined with at least a compound such as a metalloprotease inhibitor a PKC inhibitor, an anti-inflamatory agent, a soothing agent, an immunosuppressor, an ion chelating agent, an alkanolamide, an oxazolidinone and a carbamic acid derivative. The invention also concerns the use of such a composition as medicine, in particular for preventing or treating skin pathologies of allergic and/or inflammatory and/or irritative origin or resulting from a danger signal. The invention further concerns a method for cosmetic treatment of sensitive, irritated, intolerant, allergy-prone, ageing skin and/or mucosa exhibiting skin barrier disorder, or exhibiting non-pathological immunologic imbalance, which consists in applying such composition on the skin and/or mucosa.

This invention relates to the cosmetic and pharmaceutical treatment, andparticularly dermatological treatment of the skin. More particularly,this invention relates to a composition containing at least one activecompound chosen from among oxazolines, possibly in combination with atleast one other compound such as a metalloprotease inhibitor, a PKCinhibitor, an anti-inflammatory agent, a soothing agent, animmunosuppressor, an ion chelating agent, an oxazolidinone, a derivativeof carbamic acid or an alkanolamide.

Another purpose of this invention is such a composition for use as amedicine, advantageously to inhibit migration of cells such as dermaldendrocytes, monocytes, lymphocytes and particularly Langerhans cellsfor example resulting from an external stimulus or “danger signal” witha chemical, physical, biological and more particularly immune systemorigin, with a sufficiently high intensity to induce a disturbance ofthe cutaneous homeostasis. Oxazolines and their combination with ametalloprotease inhibitor, a PKC inhibitor, an anti-inflammatory agent,a soothing agent, an immunosuppressor, an ion chelating agent, anoxazolidinone, a derivative of carbamic acid or an alkanolamide andpharmaceutical compositions containing these products, are useful forthe preparation of medicine for the treatment or prevention of skinpathologies of allergic and/or inflammatory and/or irritative and/orskin discomfort origin (sensitive, reactive or intolerant skins).

Another purpose of the invention is a method for cosmetic treatment ofsensitive, irritated or intolerant skin and/or allergy-prone mucosa, oraging skin, to which a danger signal is applied, exhibiting a skinbarrier disorder, with skin rashes or exhibiting non-pathologicalimmunologic imbalance, consisting of applying such a composition to theskin and/or mucosa.

One of the main functions of the skin is to protect the body againstaggressions from the external environment. Much of this protection isprovided by cooperation of cells present in the skin, which are capableof generating an inflammatory and/or immune response directed againstthe noxious agent, in the presence of this noxious agent. These aredendritic cells, Langerhans cells (LC) of the epidermis, and dermaldendrocytes, monocytes, lymphocytes, keratinocytes, mastocytes andvascular endothelial cells.

LCs are dendritic cells derived from the bone marrow and that remain innon-lymphoid tissues such as the skin and mucosa (mouth, lung, bladder,rectum, vagina). In the skin, LCs are inserted between epidermalkeratinocytes in the suprabasal position. Ultrastructurally, they arecharacterized by the presence of a specific organelle of membraneorigin, namely the Birbeck granule. Immunohistochemically, LCs inparticular express the CD1a molecule and class II MajorHistocompatibility Complex molecules.

LCs play a determining role in immunity, as cells presenting theantigen. Experiments carried out on mice demonstrate that LCs captureantigens present in the epidermis and migrate to lymphoid tissuesdraining the skin, where they present the antigen to T cells. Initiationof the immune skin response depends on the capacity of LCs to leave theepidermis to migrate as far as the proximal ganglions. This migrationcan be influenced by different factors: the expression of adhesionmolecules, proteins from the extracellular matrix, haptens, cytokines,etc. Nevertheless, the mechanisms involved in the migration of LCs arenot yet completely elucidated. In particular, before reaching thelymphatic ganglions, LCs must not only pass through the dermoepidermaljunction (DEJ), but they also need to create a path through the dermalextracellular matrix (ECM). The DEJ is composed mainly of laminin 5,type IV and VII collagen, nidogen and perlecan. The ECM that surroundsfibroblasts in the dermis contains essentially type I and type IIIcollagens.

Maturing, and the initiation and regulation of the migration of LCsdepend on pro-inflammatory cytokines such as IL-1β (interleukin-1-beta)and TNF-α (Tumor Necrosis-alpha). The result is that any skinaggression, and particularly any inflammatory and/or irritative reactioncapable of inducing a sufficient quantity of either or both of thesecytokines, is capable of stimulating migration of LCs and thereforefacilitating the allergic reaction if these LCs are associated with anantigen.

Dermatologic type pathologies may be observed as a result of themigration of LCs following the capture of a surface antigen. In atopiceczema, LCs are capable of fixing IgEs on the surface and inducing apathological immune response. LCs play a central role in contact eczema,since they capture and treat the antigen before presenting it to Tlymphocytes. The antigen will keep it in memory and the immune reactionwill be triggered on the second contact.

Considering the above, it is highly desirable to be able to modify themigrational capacity of dermal dendrocytes, monocytes, lymphocytes,Langerhans cells (LCs), to attempt to increase the tolerance thresholdor to limit the reactivity of the allergic and/or inflammatory and/orirritated skin and the atopic and/or sensitive and/or reactive and/oruncomfortable skin. This is the problem that this invention is intendedto solve. The inventors have demonstrated that quite surprisingly andunexpectedly, compounds such as oxazolines are capable of spectacularlyinhibiting the migration of cells such as Langerhans cells, inducedparticularly by the presence of an allergen agent.

Oxazolines form a particular class of compounds for which applicationshave been known for a very long time (J. A. Frump, Chemical Reviews,1971, vol. 71, No. 5, pp 484-505). These compounds are used as coatingagents, surface protection agents, stabilizing agents, dispersingagents, particularly metallic ions such as plastifying agents,surfactants, corrosion inhibitors, anti-foaming agents or as additivesin lubricating mineral oils and adhesives. Oxazolines are also known fortheir anti-microbial and anti-fungal properties and are used in thisrespect as preserving agents. Pharmacologically, oxazolines have variousproperties such as a regulating action on the central nervous system(tranquilizers), an anti-depressive action, a vasoconstrictive agent, anappetite reduction action, an acetylcholinosterase inhibiting action,and a sedative action. However, in the past oxazolines have never beendescribed as being capable of inhibiting the migration of Langerhanscells induced particularly by the presence of an allergen agent.

This invention thus relates to a composition comprising at least oneactive compound for inhibiting the migration of Langerhans cells chosenfrom among the oxazolines group. Advantageously the compositionaccording to the invention is a cosmetic or pharmaceutical composition,and particularly a dermatological composition, comprising at least onecosmetically and pharmaceutically acceptable excipient. Oxazolinesaccording to the invention satisfy the following general formulas:

in which R₁ represents an alkyl group in C₁-C₄₀, linear or ramified,saturated or unsaturated and possibly including one or several ethylenicunsaturation(s), and one or several substitute(s) chosen from the groupformed by hydroxy (OH) and alkoxy radicals in C₁-C₆ (OC₁-C₆), and R₂,R₃, R₄ and R₅ independently represent a hydrogen atom, a hydroxyradical, or an alkyl group in C₁-C₃₀, linear or ramified, saturated orunsaturated, possibly including one or several ethylenicunsaturation(s), and one or several substitute(s) chosen from among thegroup formed by the hydroxy radical (OH), alkoxy in C₁-C₆ (OC₁-C₆)radicals and carbonyl alkoxy radicals in C₁-C₆ (COOC₁-C₆) For thepurposes of this invention, the term “alkoxy in C₁-C₆ (OC₁-C₆)” means analkoxy radical in which the alkyl group comprises 1 to 6 carbon atoms.

Preferably, the said oxazoline is a type 1 oxazoline selected from thegroup composed of 2-undecyl-4-hydroxymethyl-4-methyl-1,3-oxazoline,2-undecyl-4,4-dimethyl-1,3-oxazoline,(E)-4-,4-dimethyl-2-heptadec-8-enyl-1,3-oxazoline,4-hydroxymethyl-4-methyl-2-heptadecyl-1,3-oxazoline,(E)-4-hydroxymethyl-1-4-methyl-2-heptadec-8-enyl-1,3-oxazoline, and2-undecyl-4-ethyl-4-hydroxymethyl-1,3-oxazoline. Preferably, the saidoxazoline is 2-undecyl-4,4-dimethyl-1,3-oxazoline called OX-100 and itsformula is:

Many synthesis methods are known for preparing oxazoline compoundsaccording to the invention. Thus, these oxazolines can be prepared bychemical synthesis by making a fatty acid (or a methyl ester) and anamino-alcohol react, usually in the presence of an azeotropic agent inorder to facilitate elimination of the water (and methanol) formed.Another possible synthesis method consists of condensing a halo-amide inthe presence of a strong base or sodium carbonate (R. M. Lusskin, J.Amer. Chem. Soc., 72, (1950), 5577). Oxazolines can also be synthesizedby the reaction of epoxides on nitrites, by reaction of thionyl chlorideon hydroxyamides, or also by the action of an acid on aziridinylphosphine.

According to one embodiment of the invention, the composition may alsocomprise at least one inhibitor of the migration of Langerhans cellsselected in the group of matrix metalloprotease (MMP) inhibitors.

For the purposes of this invention, “matrix metalloprotease (MMP)inhibitor compounds” refer to any compound known to those skilled in theart for its capability of inhibiting the degradation activity of theextracellular matrix by MMPs. MMPs form a family of zinc-dependentenzymes (more than twenty have been identified and characterized) with avery preserved structure, which have the capacity of degradingcomponents of the extracellular matrix. Depending on the nature of theirsubstrate, they are classified into collagenases, gelatinases andstromelysin. They may be synthesized by different cellular types in theskin (fibroblasts, keratinocytes, macrophages, endothelial cells,eosinophilic cells, Langerhans cells, etc.). The group of MMPs is thuscomposed of four sub-classes, namely (1) collagenases, (2) gelatinises,(3) stromelysins and (4) membrane-type MMPs (MT-MMPs). The activity ofMMPs may be modulated by naturally present proteinase inhibitors such astissue inhibitors of metalloproteinases (TIMPs, and particularly TIMP-1and TIMP-2). In particular, the active compound for inhibiting migrationof Langerhans cells is a compound inhibiting at least one MMP chosenfrom among the group composed of MMP-1, MMP-2, MMP3 MMP-9, MMP-7, MMP-13and MMP-18. For the purposes of this invention, “MMP inhibitingcompound” means an active compound that inhibits the migration ofLangerhans cells, particularly tissue inhibitors of metalloproteinases(TIMPs), alpha-2-macroglobuline, plasminogen activator inhibitors, zincchelating agents, bryostatine-1, antibiotics (doxycyclines, minocylines,etc.), synthetic or natural peptides with a structure similar to thestructure of substrates of MMPs (batimastat, marimastat, etc.),retinoids (particularly non aromatic retinoids such as retinaldehyde,tretinoin and retinoic acid 9-cis, vitamin A, monoaromatic retinoidssuch as etretinate, all-trans acitretine and motrerinide, polyaromaticretinoids such as adapalene, tazarotene, tamibarotene and sulfone methylarotinoid), and antioxidants (singlet oxygen traps, etc.), anti-canceragents (or “anti-metastatic” agents), malt hydrolysates such as Colaliftmarketed by the Coletica Company, extracts of marine algae such asKelpadelie marketed by the Secma Company, shark cartilage extracts suchas the MDI complex marketed by the Atrium Company, rice peptides such asColhibin marketed by the Pentapharm Company, peptide extracts of lupin.More particularly, the MMP inhibiting compound according to thisinvention is chosen from the group composed of peptide extracts of lupinor “lupin peptides” as described in patent application FR 99 04 875deposited on Apr. 19, 1999 on behalf of the Laboratoires PharmascienceCompany. In particular, we would like to mention the peptide extractdescribed in application FR 99 04 875 under the name extract B (LU105)According to another preferred embodiment of the invention, the said MMPinhibitor is chosen from the group composed of retinoids.

According to one particular embodiment of the invention, the compositionmay also include at least one compound chosen from the group composed ofPKC inhibitors, anti-inflammatory agents, soothing agents,immunosuppressors, ion chelating agents, oxazolidinones, derivatives ofcarbamic acid, particularly (1-Hydroxymethyl-tridecyl)-carbamic acid and(1-Hydroxymethyl-undecyl)-carbamic acid and alkanolamides. This or thesecompound(s) chosen from the group composed of PKC inhibitors,anti-inflammatory agents, soothing agents, immunosuppressors, ionchelating agents, oxazolidinones, derivatives of carbamic acid,particularly (1-Hydroxymethyl-tridecyl)-carbamic acid and(1-Hydroxymethyl-undecyl)-carbamic acid and alkanolamides make itpossible to modify and/or limit the irritative or sensitizationreaction, and for some of them also even to inhibit migration ofdendritic cells, more particularly Langerhans cells, dermal dendrocytes,monocytes, lymphocytes, keratinocytes, mastocytes and endothelial cells.

For the purpose of this invention, “PKC” or “Protein Kinase C” meansenzymes that catalyze a phosphorylation reaction on a cell substrate.

When they are activated, PKCs phosphorylate specific serine or threonineresidues on protein substrates, that vary depending on the cell type. Inmany cells, activation of PKCs increases the transcription of specificgenes.

Protein Kinase C (PKC) denotes a protein coded by a family of genes (11different isoforms). In particular, it is known that these proteins areinvolved in transduction of extracellular signals mediated by growthfactors, cytokines, and a number of other biological molecules. ProteinKinase β2 (PKC-β2) appears specifically expressed by LCs of theepidermis.

Thus, any compound known to those skilled in the art as inhibiting thephosphorylation activity of PKCs can be used as a PKC inhibitingcompound according to this invention. For example, consider the exampleof polypeptides described in application WO 99 43805 (Incyte GenomicsInc.).

In particular, the PKC inhibiting compound is chosen from the groupcomposed of non-specific PKC inhibitors, specific inhibitors of isoformPCK-β2 and associations of these compounds.

More particularly, the PKC inhibiting compound is chosen from the groupcomposed of phenolic and polyphenolic compounds, procyanidins(catechines, epicatechines, etc.) alpha-amyrine, lupeol, linoleatelupeol, sterols, stanols, triterpenic alcohols and their hydrogenatedhomologues, antibiotics such as staurosporine, Ro-318425 (or2-(8)-(aminomethyl)-6,7,8,9-tetrahydropyridol(1,2-a)indol-3-yl)₃-(1-methyl-indol-ylmaleimide, HCl) as marketed by theCalbiochem Company, compounds that act by competition with physiologicalactivators of PKCs such as diacylglycerol and phorbol ester, cutaneouslipids of the (lyso)sphingolipid, lysophospholipid types such asceramides and pseudoceramides, sphingosines and phytosphingosines,sphinganines, and derivatives, precursors, analogues and homologues ofthese compounds, with natural or synthetic origin.

For the purposes of this invention, “phenolic and polyphenoliccompounds” means simple phenols, benzoquinones, phenolic acids,acetophenones, phenylacetic acids, hydroxycinnamic acids, coumarins andisocoumarins, chromones, naftoquinones, xanthones, anthraquinones,flavonoids, lignanes and neolignanes, lignines, chalcones,dihydrochalcones, aurones, flavones, flavonols, dihydroflavonols,flavanones, flavanols, flavandiols or leucoanthocyanidins,anthocyanidins, isoflavonoids, biflavonoids, proanthocyanidins andcondensed tannins.

For the purposes of the invention, “sterols” means specifically sterol,in other words the perhydro-1,2-cyclopentanophenanthrene compound with ahydroxyl group in position 3, and analogues of sterol with the generalformula (I) given below.

Thus, preferably, sterols that can be used according to the inventionpreferably satisfy the general formula given below:

in which the unsaturation shown in dashed lines in position 5corresponds to unsaturation in the case of sterols, R represents ahydrocarbonated chain, linear or ramified, unsaturated or notunsaturated, comprising 1 to 25 carbon atoms. In particular, R is chosenfrom the group composed of alkyl groups in C₁-Cl₂, alkoxy groups inC₁-C₈, alkenyl groups in C₂-C₈, alkynyl groups in C₂-C₈, cycloalkylgroups in C₃-C₈, halogenated alkenyl groups in C₂-C₈, halogenatedalkynyl groups in C₂-C₈. The term “halogenated” denotes one or severalhalogen substitutes, namely one or several atom(s) of chlorine,fluorine, bromine or iodine.

Sterols that can advantageously be used according to the inventioninclude particularly β-sitosterol, α-sitosterol, γ-sitosterol,stigmasterol, campesterol or brassicasterol and mixes of thesecompounds. For example, β-sitosterol can be used in the form of aproduct named “Ultra” (comprising mainly β-sitosterol) as marketed bythe Kaukas Company. Examples of mixes of sterols include the productcalled “Generol” comprising mainly β-sitosterol (about 50% by weight),stigmasterol, brassicasterol or campesterol as marketed by the CognisCompany, and the “Primal” product made by the Kaukas Company.

Triterpenic alcohols that can advantageously be used according to theinvention include in particular β-amyrine, erythrodiol, taraxasterol,cycloartenol, 24-methylenecycloartanol, lupeol, lanosterol and mixes ofthese compounds.

For the purposes of this invention, “hydrogenated homologues” of atriterpenic alcohol means corresponding triterpenic alcohol compound(s)for which any unsaturated bond(s) that is (are) present have beenhydrogenated (in other words transformed into a saturated bond) usingmethods well known to those skilled in the art.

More particularly, the PKC inhibiting compound is chosen from the groupcomposed of sphingolipids and lysophospholipids such as:

-   -   ceramics    -   sphingosines    -   galactocerobrosides    -   psychosines    -   sulfatides    -   lysosulfatides    -   sphyngomyelins, and    -   lysosphingomyelins.

Note also that cutaneous lipids of the sphingolipid and lysophospholipidtypes can be used in particular as a PKC inhibiting compound.

Some of the most elementary sphingolipids that can be used aresphingosine (D erythro dihydroxy 1,3 amino 2 octadecene 4t) and itsisomers, and phytosphingosine (D ribo trihydroxy 1,3,4 amino 2octadecane) and its isomers. But lysosphingolipids (includinglysosulfatide and psychosine), solfogalactosylsphingosine, sphinganine(2-amino 1,3 octadecane diol) and sphingomyelins can also be used.

Phospholipids in the phosphatidylamino-alcohol and phosphatidylpolyolfamilies can be used. The phosphatidylamino-alcohols group includesparticularly phosphatidylethanolamines (or phosphatidylcolamines),phosphatidylcholines, phosphatidylserines,N-acylphosphatidylethanolamines. The phosphatidylpholyols group includesphosphatidylcholinositols, diphospho-inositides,lysodiphospho-inositides, phosphatidylglycerols and cardiolipids.

Note also more particularly that PKC inhibiting compounds used mayinclude ceramides, particularly ceramides of the intercorneocyte cementof the epidermis and ceramide precursors, namely sphingosine andphytosphingosine.

In general, ceramides may be synthesized chemically (they are frequentlycalled pseudo-ceramides), or they may be of animal origin (relativelyhigh concentrations of sphingolipids are present in the encephalus andthe spinal cord of mammals) or plant origin (namely cerebrosides andanother glycosylated sphongolipids) or derivates of yeasts(stereochemical configuration identical to that of ceramides naturallypresent in the human skin).

Ceramides of the intercorneocyte cement of the epidermis may beseparated by conventional methods (thin layer chromatography) into sixfractions corresponding to compounds that differ by the nature of fattyacids and the nature of the base involved (sphingosines, unsaturated, orphytosphingosines, saturated). The following table 1 illustrates thecorresponding structures in these fractions, according to the Werts andDowning classification. Fraction 6 itself may be sub-divided by finermethods into two entities, ceramides 6a and 6b. TABLE 1 the six mainfractions of ceramides in the epidermis

1

2

3

4

5

6a

6b

Thus, ceramides 1, the least polar, comprise a very special structurethat is repeated in ceramide 6a: an omega-hydroxyacid with a long chainamidifying the base, and attached at its omega end by an ester bond toanother fatty acid (O-acylceramides). In the case of fraction 1, fattyacids bonded to sphingosine are essentially in C24, C26, C30, C32 andC34 and they may be saturated, monoethylenic (mainly for C30, C32 andC34) or diethylenic (c32 and especially C34). The fatty acid attached tothe omega end of the previous item, it is predominantly linoleic acidfor ceramides 1, the essential role of the epidermis hybrid barrierfunction is well known.

Fraction 2 has a more classical structure (sphingosines ordihydrosphingosines bonded by an amide bond to a fatty acid, mainly C20to C28) is the most frequent.

Fraction 3 is fairly similar, the only difference applying to the natureof the base, which in this case is represented essentially by saturatedphytosphingosines.

Fractions 4 and 5 are characterized essentially by the presence ofalpha-hydroxyacids bonded to a sphingosine.

Fraction 6b is similar to fractions 4 and 5, comprising an alphahydroxyacid, but bonded to a saturated phytosphingosine.

Fraction 6a, like the ceramide 1, comprises the characteristic patternthat is only located in ceramides in the epidermis, in other words theester bond between the omega hydroxyl of a fatty acid bonded to asphingosine, and the carboxylic group of a terminal fatty acid which inthis case is an alpha-hydroxyacid rather than linoleic acid.

Note also phytoceramides (ceramides based on phytosphingosin), syntheticcholesterol-ceramides, galacto or gluco cerebrosides.

Finally, the PKC inhibiting compounds that may be used according to thisinvention include sphingosine that is present in the natural state inthe skin, and also plays an important role in the barrier function ofthe stratum corneum, as a precursor of sphingolipids (ceramides andsphingoglycolipids). It may be derived from a biological source such ascattle brain extracts or by a synthetic method starting from serine forexample as described in the article by Newman, J. Am. CHEM., 95 (12):4098 (1973). More particularly, note the isomer forms of sphingosine,D-erythro, L-threo, L-erythro and D-threo. The D-erythro form is theform most frequently present in nature.

According to this invention, PKC inhibiting compounds that can be usedinclude isomers, derivatives (salts, complexes, etc.), analogues,homologues, precursors and metabolites of the PKC inhibiting compoundsdescribed above.

The anti-inflammatory agents that can be used in the context of thisinvention in association with oxazolines are Non SteroidalAnti-Inflammatory Drugs (NSAID).

The soothing agents that can be used in the context of this invention incombination with oxazolines are advantageously derivatives of liquoriceand derivatives of alpha-bisabolol.

The immunosuppressors that can be used in the context of this inventionin association with oxazolines are advantageously tacrolimus,pimecrolimus, and cyclosporine.

The ion chelating agents that can be used in the context of thisinvention in association with oxazolines are advantageously chemicalchelating agents advantageously chosen from the group composed ofethylenediamine-tetraacetic acid (EDTA) and salts of sodium, potassium,calcium disodium, diammonium, triethanololamine (TEA-EDTA), hydroxyethylethylene diamine tetraacetic acid (HEDTA) and its trisodium salt,diethylenetriamine pentacetic acid (DTPA) and mixes of them. The ionchelating agents may also be biological chelating agents advantageouslychosen from the group composed of metallothionein, transferrin,lactoferrin, calmoduline, chitosane methylene phosphonate and mixes ofthem.

The chelated ions are advantageously the Na⁺, K⁺, Ca²⁺, Cl, Ni²⁺, Co⁺,Co²⁺, Zr²⁺, Zr⁴⁺ ions, but also chromium ions at oxidation level II andIII such as Cr²⁺, Cr²⁺ and Cr₂O₇ ²⁻.

The alkanolamides that can be used in the context of this invention inassociation with oxazolines are advantageously alkanolamides satisfyingthe following general formula:

in which R₁ represents an alkyl group in C₁-C₄₀ comprising 0 to 6unsaturations and possibly comprising at least one substitute chosenfrom the group formed by hydroxyl radicals (OH), alkoxy radicals inC₁-C₆ (OC₁-C₆) and carbonyl alkoxy radicals in C₁-C₆ (COOC₁-C₆).

R′ and R″ independently represent a hydrogen atom, a methyl group, ahydroxyl group, an alkyl group in C₂-C₂₀ comprising 0 to 6 unsaturationsand possibly comprising at least one substitute chosen from the groupformed by hydroxyl radicals (OH) and alkoxy radicals in C₁-C₆ (OC₁-C₆),provided that when R′ represents a hydroxyl group, R″ represents ahydrogen or an alkyl group in C₁-C₆ comprising from 0 to 3 unsaturationsand possibly at least one substitute chosen from the group formed byhydroxyl radicals (OH), alkoxy radicals in C₁-C₆ (OC₁-C₆) and carbonylalkoxy radicals in C₁-C₆ (COOC₁-C₆).

R₂ represents a hydrogen atom, a methyl group, an alkyl group in C₂-C₂₀comprising 0 to 6 unsaturations and possibly at least one substitutechosen from the group formed by hydroxyl radicals (OH), alkoxy radicalsin C₁-C₆ (OC₁-C₆) and carbonyl alkoxy radicals in C₁-C₆ (COOC₁-C₆) Forthe purposes of this invention, the term “alkoxy radical in C₁-C₆(OC₁-C₆)” means an alkoxy radical in which the alkyl group comprisesbetween 1 and 6 carbon atoms.

Advantageously, the radical R₁ represents a saturated linear alkyl groupcomprising 2 to 40 carbon atoms (in C₂-C₄₀), advantageously 6 to 22carbon atoms (in C₆-C₂₂), and even more advantageously from 8 to 18carbon atoms (in C₈-C₁₈), and even more advantageously from 10 to 16carbon atoms (in C₁₀-C₁₆).

In another embodiment of the invention, the radical R₁ represents analkyl group comprising 1 to 40 carbon atoms (in C₁-C₄₀) advantageously 2to 40 carbon atoms (in C₂-C₄₀), preferably 6 to 22 carbon atoms (inC₆-C₂₂) and even more advantageously from 8 to 18 carbon atoms (inC₈-C₁₈), comprising 1 to 6 unsaturations and possibly including at leastone hydroxyl, alkoxy, or carbonyl alkoxy radical as defined above.

According to one embodiment of the invention, R′ and R″ independentlyrepresent a hydrogen atom, a methyl group, a linear alkyl groupsaturated in C₂-C₂₀.

According to another embodiment of the invention, R₂ represents ahydrogen atom, a methyl group or a linear alkyl group saturated inC₂-C₂₀.

According to one advantageous variant of the invention, the saidalkanolamide is the alkanolamide called AK100 with the followingformula:

The derivatives of carbamic acid that can be used in the context of thisinvention in association with oxazolines are advantageously derivativesof carbamic acid satisfying the following general formulas:

in which:

-   R₁ represents a hydrogen atom or an alkyl group in C₁-C₃₀, linear or    ramified, saturated or unsaturated, possibly including one or    several ethylenic and/or acetylenic unsaturations, and one or    several hydroxy substitutes (OH);-   R₂ and R′₂ independently represent a hydrogen atom or an alkyl group    in C₁-C₃₀, linear or ramified, saturated or unsaturated, possibly    including one or several ethylenic and/or acetylenic unsaturations,    and one or several hydroxy substitutes (OH);-   R₃ and R₁₃ independently represent a hydrogen atom or an alkyl group    in C₁-C₃₀, linear or ramified, saturated or unsaturated, possibly    including one or several ethylenic and/or acetylenic unsaturations,    and one or several hydroxy substitutes (OH);-   R₄ and R₅ independently represent a hydrogen atom or an acyl group    of the RxCO type in which Rx is an alkyl radical in C₁-C₃₀, linear    or ramified, saturated or unsaturated, possibly including one or    several ethylenic and/or acetylenic unsaturations, and one or    several hydroxy substitutes (OH);

According to one embodiment, R₁ represents a hydrogen atom.

According to another embodiment, R₂ represents a linear alkyl groupsaturated in C₈-C₂₂, advantageously in C₉-C₁₈, even more advantageouslyin C₉-C₁₃, and even more advantageously in C₁₁-C₁₃ and/or R′₂ representsa hydrogen atom.

According to another embodiment, R₃ and R′₃ represent a hydrogen atom.

According to another embodiment, R₄ and R₅ represent a hydrogen atom.

In one particular embodiment, R₁ represents a hydrogen atom, R₂represents a linear alkyl group saturated in C₈-C₂₂, advantageously inC₉-C₁₈, even more advantageously in C₉-C₁₃ and even more advantageouslyin C₁₁-C₁₃, and R₁₂, R₃, R₁₃, R₄ and R₅ represent a hydrogen atom.

Advantageously, the derivative of carbamic acid is chosen from the groupcomposed of (1-Hydroxymethyl-tridecyl)-carbamic acid and(1-Hydroxymethyl-undecyl)-carbamic acid.

(1-Hydroxymethyl-tridecyl)-carbamic acid can be represented by thefollowing formula:

Oxazolidinones that can be used in the context of this invention inassociation with oxazolines are advantageously oxazolidinones satisfyingthe following general formulas:

in which:

-   R₁ represents a hydrogen atom or an alkyl group in C₁-C₃₀, linear or    ramified, saturated or unsaturated, possibly comprising one or    several ethylenic and/or acetylenic unsaturations, and one or    several hydroxy substitutes (OH);-   R₂ and R′₂ independently represent a hydrogen atom or an alkyl group    in C₁-C₃₀, linear or ramified, saturated or unsaturated, possibly    including one or several ethylenic and/or acetylenic unsaturations,    and one or several hydroxy substitutes (OH);-   R₃ and R′₃ independently represent a hydrogen atom or an alkyl group    in C₁-C₃₀, linear or ramified, saturated or unsaturated, possibly    including one or several ethylenic and/or acetylenic unsaturations,    and one or several hydroxy substitutes (OH);

According to one embodiment, R₁ represents a hydrogen atom.

According to another embodiment, R₂ represents a linear alkyl groupsaturated in C₈-C₂₂, advantageously in C₉-C₁₈, even more advantageouslyin C₉-C₁₂ and even more advantageously in C₁₀-C₁₁, and/or R₁₂ representsa hydrogen atom.

According to another embodiment, R₃ and R₁₃ represent a hydrogen atom.

In one particular embodiment, R₁ represents a hydrogen atom, R₂represents a linear alkyl group saturated in C₈-C₂₂, advantageously inC₉-C₁₈, even more advantageously in C₉-C₁₂ and even more advantageouslyin C₁₀-C₁₁, and R′₂, R₃ and R′₃ represent a hydrogen atom.

Advantageously, the oxazolidinone is chosen from the group composed of4-dodecyl-oxazolidin-2-one, 3,4-didodecyl-oxazolidin-2-one and4,5-didodecyl-oxazolidin-2-one.

4-dodecyl-oxazolidin-2-one can be represented by the following formula:

3,4-didocyl-oxazolidin-2-one may be represented by the followingformula:

4,5-didodecyl-oxazolidin-2-one may be represented by the followingformula:

Alkanolamides, oxazolidinones and derivatives of carbamic acid arecompounds inhibiting the migration of Langerhans cells.

The composition according to the invention is characterized in that theconcentration of oxazoline is advantageously between about 0.001 andabout 10% by weight, and more particularly between 0.01 and 3% byweight, compared with the total weight of the composition.

The composition according to this invention is advantageously a cosmeticor pharmaceutical composition, and particularly a dermatologicalcomposition. The composition according to the invention may beformulated in different preparations adapted to topical administration,oral administration or rectal administration, or to parenteraladministration. Preferably, the different preparations are adapted totopical administration and include creams, pomades, lotions, oils,patches, sprays and any other products for external application.Administration modes, posologies and optimum galenic forms of thecompounds and compositions according to the invention may be determinedaccording to criteria usually used in preparation of a cosmetic orpharmaceutical treatment, preferably dermatological, adapted to apatient such as for example the age or body weight of the patient, theseverity of his general condition, his tolerance to treatment, observedside effects, the skin type. Depending on the required administrationtype, the composition and/or active compounds according to the inventionmay also comprise at least one cosmetically acceptable orpharmaceutically acceptable excipient, and particularly adermatologically acceptable excipient. Preferably, an excipient adaptedfor administration by external topical method will be chosen. Thecomposition according to this invention may also comprise at least oneadditive cosmetically or pharmaceutically known to those skilled in theart, chosen from among thickeners, preservation agents, perfumes,coloring agents, chemical or mineral filters, moisturizing agents,mineral water, etc.

This invention also relates to the compositions described above fortheir use as medicine.

This invention also relates to the use of at least one active compoundchosen from among the oxazolines group as defined above or a compositionaccording to the invention for the preparation of a medicine designed toinhibit migration of dendritic cells, dermal dendrocytes, monocytes,lymphocytes, keratinocytes, mastocytes and endothelial cells.

According to one particular embodiment of the invention, the medicine isintended to inhibit migration of Langerhans cells.

Advantageously, the said medicine is intended for the treatment orprevention of allergic and/or inflammatory and/or irritative reactionsor pathologies of the skin and mucosa, particularly of the mouth, thelungs, bladder, rectum and vagina.

Advantageously according to this invention, the medicine is intended forthe treatment and/or prevention of reactions or pathologies of the skinand/or mucosa following migration of cells such as Langerhans cells,induced by a danger signal. For the purposes of this invention, a“danger signal” means any signal that in particular leads to theproduction of inflammatory cytokines or any true immunologic signal suchas penetration of an allergen.

According to one embodiment of this invention, the medicine is intendedfor the treatment and/or prevention of reactions or pathologies inducedby chemical or metallic haptens.

According to another embodiment of this invention, the medicine isintended for the treatment or prevention of sensitive and/or reactiveand/or uncomfortable and/or intolerant skin and/or mucosa, and/or skinand/or mucosa exhibiting a barrier disorder and/or exhibiting animmunologic imbalance related to intrinsic aging, extrinsic aging (sun,pollution) or hormonal aging.

It has been shown that aging of the skin causes a modification to theimmunity status of the skin and that the initial location of immunologiccells can be modified as a result of uncontrolled migration.

The composition according to the invention, and the active compoundsaccording to the invention, can reduce the immune response induced bymigration of LCs that had fixed IgEs on the surface. This is why thisinvention also relates to the use of a composition according to theinvention and intended to inhibit the migration of Langerhans cells orat least one active compound chosen from among the oxazolines group asdescribed above for the treatment or prevention of atopic eczema. Thecomposition according to the invention and active compounds according tothe invention, are also intended for the treatment or prevention ofcomplex eczema, provided that they can reduce an immune response inducedparticularly by capture of an antigen, treatment and presentation ofthis antigen by LCs to T lymphocytes.

The composition according to the invention, and active compoundsaccording to the invention, are also used for the treatment and/or theprevention of inflammatory pathologies, particularly inflammatorydermatitis such as psoriasis, irritative dermatitis, auto-immunediseases, prevention of photo-immuno-suppression or graft rejection.“Photo-immuno-suppression” for the purposes of this invention means areduction of the immune response induced by solar ultra-violet rays andparticularly by B ultra-violet rays.

Finally, another purpose of this invention is to use a compositionaccording to the invention, and active compounds according to theinvention, to reduce the allergizing and/or irritant nature of acomposition that may be a pharmaceutical preparation or a cosmeticpreparation or a perfume. The term “allergenic nature” means thecapacity of some compounds contained in the said preparation to behavelike allergens, in other words compounds capable of inducing animmediate and/or an inflammatory hyper-sensitivity reaction.

In the various uses mentioned above of the active compound chosen fromthe oxazolines group as defined above, the active compound may be usedin association with at least one Langerhans cell migration inhibitorselected from among the group composed of matrix metalloprotease (MMP)inhibitors, PKC inhibitors, anti-inflammatory agents, soothing agents,immunosuppressors, ion chelating agents, oxazolidinones, derivatives ofcarbamic acid and alkonolamides as defined above.

The composition and active compounds according to the invention areadvantageously intended for use in cosmetology. This invention alsorelates to a method of cosmetic treatment of the skin and/or mucosaselected from among sensitive, irritated, intolerant skin and/or mucosa,or allergy-prone skin and/or mucosa, or aging skin and/or mucosa or towhich a danger signal is applied, exhibiting a barrier disorder, withskin rashes, or exhibiting a non-pathological immunologic imbalancerelated to intrinsic aging, extrinsic aging or hormonal aging,characterized in that it consists of applying a cosmetic compositionaccording to the invention or at least one active compound chosen fromamong the oxazolines group as defined above, onto the skin and/ormucosa. The active compound chosen in the oxazolines group as definedabove may also be applied in association with at least one othercompound selected from the group composed of matrix metalloprotease(MMP) inhibitors, PKC inhibitors, anti-inflammatory agents, soothingagents, immunosuppressors, ion chelating agents, oxazolidinones,carbamic acid derivatives and alkanolamides as defined previously. Inthe context of the cosmetic treatment method according to thisinvention, the non-pathological immunologic imbalance is a temporary orpermanent unbalance of the skin immunity function without being severe.

Other characteristics and advantages of the invention are given in theremainder of the disclosure with the examples given below. Theseexamples refer to the figures given below. These figures and examplesare intended to illustrate this invention and may in no case beinterpreted as being capable of limiting its scope.

FIGURES

FIG. 1: migration index of Langerhans cells freshly isolated from humanskin and activated by DNSB. Effect of the oxazoline molecule OX100(2-undecyl-4,4-dimethyl-1,3-oxazoline). (1) control cells; (2) cellssensitized by DNSB hapten; (3) cells sensitized by DNSB hapten+OX100 (1μM).

FIG. 2: Percent (%) of migration of dendritic cells derived from bloodfrom the umbilical cord, after activation by hapten. Effect of theoxazoline molecule OX100 (2-undecyl-4,4-dimethyl-1,3-oxazoline). (1)cells sensitized by hapten BB; (2) cells sensitized by BB hapten+OX100(1 μM).

EXAMPLES Example 1 Example Composition According to this Invention

% by weight Water QSP 100 Hydrogenated polydecene 8 to 15 Glycerine 8 to15 Dicaprylyl carbonate 3 to 7  Lauryl glucoside 1.5 to 3  Polyglyceryl-2 dipolyhydroystereate 0.2 to 3   Peptide extract of lupin(hydrolyzed protein) Acrylate/Copolymer alkyl acrylate 0.4 in C₁₀₋₃₀Sodium hydroxymethylglycinate 0.4 Xanthane gum 0.3 Oxazoline OX100 0.01to 0.7  Sodium hydroxide  0.07 Citric acid  0.03

Example 2 Study of the Activity of OX100 on Inhibition of Migration ofLCs Freshly Isolated from Fragments of Human Skin

Equipment and Methods

Obtaining Langerhans Cells

Epidermal cell suspensions were obtained by enzymatic treatment (0.05%trypsine for 18 h at +4° C.) of fragments of normal human skin takenfrom plastic surgery. The suspensions obtained contain an average of 2to 4% of LC. Obtaining suspensions containing an average of 70% of LC isbased on the principle of centrifuging on density gradient (Lymphoprep™)and elimination of keratinocytes.

Preparation of Media

The basic medium chosen for the entire study was PRMI 1640 (Gibco BRL,France). The OX100 molecule supplied by Pharmascience, with aconcentration of 10-2 M in solution in DMSO (Dimethyl Sulfoxide) wasdiluted in RPMI-1640 and tested at 1 μM.

Sensitization of LCs

The sensitizing agent was DNSB (Sigma Aldrich), a soluble form of DNCB(dinitro-chloro-benzene) solubilized in RPMI-BSA and used at aconcentration of 50 μM.

Migration of LCs

A culture chamber system with two compartments (Falcon, BectonDickinson, France) was used. The upper compartment is separated from thelower compartment by a membrane with 8 μm porosity, on which 50 μg/cm²Matrigel was deposited. The membrane was then covered by proteinsforming a film equivalent to a base membrane (laminine, IV collagen,nidogen, entactin, heparane sulfate proteoglycanes). The cells includedin the RPMI-BSA medium alone or in the presence of different productsare deposited in the upper compartment. The supernatant culture ofnormal human fibroblasts is added in the lower compartment. After 18 hincubation at 37° C., the number of living cells that passed through theMatrigel and that are located in the lower compartment is counted undera microscope (the LCs are easily identifiable by their dendritic form).Each test is carried out in triplicate.

Results

Table 2 below shows the results illustrated by the histogram in FIG. 1.TABLE 2 LC migration index 1 2 3 Migration 1 2.55 0.98 indexLegend for table 2 and histogram in FIG. 1:1: Control cells2: Cells sensitized by DNSB hapten3: DNSB + OX100 (1 μM).

Migration of LCs

The results represent the ratio between the number of cells thatmigrated in the presence of DNSB +/−OX100 and the number of cells thatmigrated under normal conditions (insensitive and untreated controlcells). LCs freshly isolated from the epidermis do not have a highmigration capacity. In the expression of the results, the migrationalcapacity of control LCs (not treated and not sensitized) is arbitrarilyset equal to 1.

The treatment with cells with DNSB hapten stimulated migration of LCssignificantly (+155%) compared with normal unstimulated cells (controlcells). OX100 at a concentration of 1 μM significantly inhibitsmigration of LCs induced by DNSB. The cells thus treated have amigration index comparable to the migration index of unsensitizedcontrol cells.

The inventors have demonstrated that, quite surprisingly, OX100significantly inhibits migration of LCs when freshly isolated LCs areused placed in a culture chamber system with two compartments (enablingcellular migration). Under the experimental conditions used by theinventors, cells treated by OX100 have a migration index comparable tothat of unsensitized control cells.

Example 3 Study of the OX100 Activity on Inhibition of Migration ofDendritic Cells Generated In Vitro from CD34+ Precursors Derived fromBlood from the Umbilical Cord

Equipment and Methods

In Vitro Langerhans-Like Generation

Mononucleated cells were obtained from blood from the umbilical cord ofhealthy donors by centrifuging on Ficoll. The CD34+ cells were thenpurified by immunoselection using a specific antibody and magnetic balls(Miltenyi Biotech, Germany). The CD34+ cells were cultivated in thepresence of GM-CSF (100 ng/ml), TNF-α (2.5 ng/ml) in RPMI to which 10%calf fetus serum was added for 5 days. TGF-β1, a factor that encouragesdifferentiation of cells to the Langerhans cells method, was added onthe 5^(th) day of culture.

Preparation of Media (Ditto Example 2).

Sensitization of LCs

Cells were treated by hapten BB on the 7^(th) day (Brandowski base, 1.17μg/ml) for 24 h, and were then subjected to the migration test.

Migration of LCs (Ditto Example 2).

Results

The results of two independent experiments are given in table 3 belowand are illustrated by the histogram in FIG. 2. TABLE 3 Percentage ofdendritic cells generated in vitro that migrated 1 2 Experiment 1 17 12Experiment 2 24 20.3Legend for table 3 and histogram in FIG. 2:1: Cells sensitized by hapten BB2: BB + OX100 (1 μM).

Migration of LCs

The results represent the percentage of cells that migrated in thepresence of the different tested products. The percentage is calculatedby taking the ratio of the number of cells recovered in the lowercompartment of the migration chamber, to the number of cells subjectedto migration. OX100 inhibits the migration of dendritic cells by 29 and15% in experiments 1 and 2 respectively.

At a concentration of 1 μM, the OX100 significantly inhibits migrationof dendritic cells generated in vitro and activated by hapten BB.

Example 4 Study of the Activity of Oxazoline OX100, Alone or inAssociation with LU105, on Inhibition of Migration of Dendritic Cells inMice

Equipment and Methods

Reagents

FITC (Fluoresceine isothiocyanate, Sigma, St. Louis, Mo.) wasextemporaneously diluted in an acetone mix (dibutylphthalate (1:1)).

Inhibitors

Oxazoline OX100 and LU105 (LU 105 is an MMP inhibitor, corresponding toa peptide extract of white lupin marketed by the Expanscience Companyunder the brand name Actimp 193®) were supplied by “LaboratoiresExpanscience” and formulated alone or association with each other in aninert vehicle compatible with a topical application (oxazoline OX100(0.1%)±LU105 (2%)). The different formulations were applied on the earsof mice twice per day for 4 consecutive days. 1.5% of FITC was appliedon both ears (one treated and the other not treated (Control)) threehours after the last application.

Migration of Langerhans cells (LC) and dendritic cells (DC) in mice.

The effect of the two molecules was evaluated in vivo in mice. 1.5% FITC(2×5 μl) was applied on the skin of both ears. 24 h later, the mice weresacrificed and a cellular suspension was prepared from auricular andcervical ganglions (draining ganglions, hereinafter denoted GL) or fromthe poplital ganglions (non-draining ganglions, negative control). Thetissues were cut and cells separated by filtration (100 μm filter,Falcon; Becton Dickinson) and then washed. The cells were thencentrifuged for 10 minutes at 600×g (m×s⁻²) on a metrizamide gradient(14.5% in RPMI 1640; 7.5% SVF). The interface cells were retrieved,rinsed and then marked with an anti-CDS86 PE-conjugated, biot-MHC CLIImAbs AC plus streptavidine-Cya (PharMingen) and analyzed by fluxcytometry. Only the FITC⁺, PE⁺ and Cya⁺ cells are counted since theyrepresent the population of cells that migrated from the skin to GLsfollowing the application of hapten.

Results

Topical application of the vehicle alone did not cause any modificationto the number of FITC+ DCs in LGs. Therefore the vehicle does not haveany effect on the migratory capacities of DCs.

Table 4 below shows the results for migration of DCs. TABLE 4 OXAZOLINEOXAZOLINE LU105 OX100 (0.1%) + OX100 (0.1%) (2%) LU105 (2%) Migration 3040 90 inhibition in %

Migration of DCs at LGs after FITC hapten was applied, is inhibited insimilar proportions by a 0.1% content of oxazoline OX100 and a 2%content of LU105, there being no significant difference.

When the two types of molecules are associated, this inhibition isalmost complete. In conclusion, it has been quite surprisinglydemonstrated that if a model for mice sensitized by FITC hapten is used,oxazoline OX100 significantly inhibits migration of DCs to LGs.Furthermore, oxazoline OX100 and LU105 act in synergy to inhibit themigration of DCs in the sensitized mouse.

Example 5 Study of the Activity of Oxazoline OX100 Alone or inAssociation with OX100, on Inhibition of the Migration of DendriticCells in Mice

Equipment and Methods

Reagents

FITC (Fluoresceine isothiocyanate, Sigma, St. Louis, Mo.) was dilutedextemporaneously in a mixture of acetone and dibutylphthalate (1:1).

Inhibitors

Oxazoline OX100 and AK100 (described above) were supplied by“Laboratoires Expanscience” and formulated alone or in association in aninert vehicle compatible with a topical application [OX100 (0.05%)±AK100(0.05%)]. The different formulations were applied on the ears of micetwice per day for 4 consecutive days. Three hours after the lastapplication, 1.5% of FITC was applied on both ears (one treated and theother not treated (Control)).

Migration of Langerhans cells (LC) and dendritic cells (DC) in mice.

The effect of the two molecules was evaluated in vivo in mice. 1.5% FITC(2×5 μl) was applied on the skin of both ears. 24 h later, the mice weresacrificed and a cellular suspension was prepared from auricular andcervical ganglions (draining ganglions, hereinafter denoted GL) or fromthe poplital ganglions (non-draining ganglions, negative control). Thetissues were cut and cells separated by filtration (100 μm filter,Falcon; Becton Dickinson) and then washed. The cells were thencentrifuged for 10 minutes at 600×g (m×s⁻²) on a metrizamide gradient(14.5% in RPMI 1640; 7.5% SVF). The interface cells were retrieved,rinsed and then marked with an anti-CDS86 PE-conjugated, biot-MHC CLIImAbs AC plus streptavidine-Cya (PharMingen) and analyzed by fluxcytometry. Only the FITC⁺, PE⁺ and Cya⁺ cells are counted since theyrepresent the population of cells that migrated from the skin to GLsfollowing the application of hapten.

Results

Topical application of the vehicle alone did not cause any modificationto the number of FITC+ DCs in LGs. Therefore the vehicle does not haveany effect on the migratory capacities of DCs.

Table 5 below shows the results for migration of DCs. TABLE 5 OX100AK100 OX100 (0.05%) + (0.05%) (0.05%) AK100 (0.05%) Migration 15 15 40inhibition in %

Migration of DCs at LGs after FITC hapten was applied, is inhibited insimilar proportions by a 0.05% content of OX100 and a 0.05% content ofAK100, there being no significant difference.

When the two types of molecules are associated, this inhibition isgreater. In conclusion, it has been quite surprisingly demonstrated thatif a model of mice sensitized by FITC hapten is used, oxazoline OX100significantly inhibits migration of DCs to LGs. Furthermore, OX100 andAK100 act in synergy to inhibit the migration of DCs in the sensitizedmouse.

Example 6 Evaluation of the Effects of a Cosmetic Day Cream ComprisingOxazoline OX100 for a Hypersensitive, Irritated Skin or Skin withAllergic Predisposition

A cosmetic day cream comprising 0.1% by weight of OX100 and 2% by weightof peptide extract from white lupin, LU105, as a function of the totalweight of the cream, was tested on human volunteers, with thecooperation of dermatologists.

The main purposes were to evaluate the clinical efficiency and cosmeticacceptability of the said day cream in the context of normal use of theproduct.

The test product was provided to the practitioner with the necessarypublic information, and the Dermatologist proposed it to his patientspecifying sufficient daily application methods, namely at least 2applications per day. The product was applied to the face morning andevening on a clean and dry skin.

The total duration of the study for each volunteer was 4 weeks with twoobservations, recorded before and then after this 4-week applicationperiod.

The volunteer was non-directively questioned about the possibleoccurrence of undesirable local effects during the final visit.

The tests were carried out in accordance with the protocol described on73 women, including 37 with sensitive skin and 36 with irritated skin.

The results were evaluated on a scale varying from 0 to 9. A mark of 0corresponds to zero change of the skin before and after the treatment, amark varying from 1 to 3 corresponds to a slight change of the skinbefore and after the treatment, a mark from 4 to 6 corresponds to amoderate change to the skin before and after the treatment, and a markfrom 7 to 9 corresponds to a large change to the skin before and afterthe treatment.

Table 6 below contains the results. TABLE 6 Group Group with with Globalsensitive irritated sample skin skin Dermatological (73 (37 volun- (36volun- clinic evaluation women) teers) teers) Erythema Average mark outof 3.89 4.16 3.61 10 on D0 Average mark out of 1.73 1.95 1.50 10 on D30% change from D0 to −56% −53% −58% D30 Dryness Average mark out of 4.334.62 4.03 10 on D0 Average mark out of 1.47 1.57 1.36 10 on D30 % changefrom D0 to −66% −66% −66% D30 Desqua- Average mark out of 2.71 2.59 2.83mation 10 on D0 Average mark out of 0.75 0.59 0.92 10 on D30 % changefrom D0 to −72% −77% −68% D30 Edema Average mark out of 0.90 1.08 0.7210 on D0 Average mark out of 0.10 0.11 0.08 10 on D30 % change from D0to −89% −90% −88% D30 Vesicles Average mark out of 0.40 0.73 0.06 10 onD0 Average mark out of 0.03 0.05 0.00 10 on D30 % change from D0 to −93%−93% −100%  D30 Roughness Average mark out of 1.71 1.94 1.47 10 on D0Average mark out of 0.38 0.49 0.28 10 on D30 % change from D0 to −78%−75% −81% D30 Pruritus Average mark out of 10 2.96 3.16 2.75 on D0Average mark out of 10 0.63 0.57 0.69 on D30 % change from D0 to D30−79% −82% −75% Smarting Average mark out of 10 2.95 3.62 2.25 on D0Average mark out of 10 0.59 0.68 0.50 on D30 % change from D0 to D30−80% −81% −78% Burning Average mark out of 10 3.16 3.97 2.33 sensationon D0 Average mark out of 10 0.49 0.57 0.42 on D30 % change from D0 toD30 −84% −86% −82% Pain Average mark out of 10 0.81 0.97 0.64 on D0Average mark out of 10 0.07 0.05 0.08 on D30 % change from D0 to D30−92% −94% −87% Global evaluation of the dermatologist (average mark outof 10) Improvement of objective signs 6.11 6.36 6.23 Improvement ofsubjective symptoms 6.3  6.75 6.52 Product adapted to care of the 6.387.14 6.75 sensitive, irritated or allergic skin

These various results show that the said day cream significantlyimproves the condition of hypersensitized, irritated skin andallergy-prone skin.

Thus the said cream, formulated without perfume or coloring agent,efficiently moisturizes the upper layers of the epidermis and providesan appropriate response to hypersensitive, irritated skins andallergy-prone skin.

The tested cream was also evaluated by consumers as being very pleasantto use with good cosmetic qualities such as a pleasant texture, anon-fatty feel, and a feeling of comfort after application. In terms ofefficiency, the volunteers perceive a reduction in the reactivity of theskin to aggressive polluting or drying environments, a reduction inirritation and subjective symptoms of the sensitive skin, an improvementto the tolerance to cosmetics (washing products), a protective andsoothing effect immediately and in the long term (75% of thepopulation), a drop in sudden discomfort (73%), and an improvement inthe tolerance threshold (70%). Globally, 89% of them were satisfied withthe tested cream.

In conclusion, it has thus been demonstrated quite surprisingly, thatOX100 in association with LU105 inhibits almost all migration of DCs toLGs. Moreover, OX100 and LU105 act in synergy to inhibit migration ofDCs in a sensitized mouse.

It has thus quite surprisingly been demonstrated that the sameproportions of OX100 and LU105 incorporated into a cosmetic cream enableeffective moisturization of the upper layers of the epidermis andprovide an appropriate solution to hyper sensitive, irritated skin orallergy-prone skin.

1. Composition comprising at least one active compound to inhibitmigration of Langerhans cells chosen from the oxazolines group. 2.Composition according to claim 1, characterized in that the saidoxazolines satisfy the following general formulas:

in which R₁ represents an alkyl group in C₁-C₄₀, linear or ramified,saturated or unsaturated and possibly including one or several ethylenicunsaturation(s), and one or several substitute(s) chosen from the groupformed by hydroxy (OH) and alkoxy radicals in C₁-C₆ (OC₁-C₆), and R₂,R₃, R₄ and R₅ independently represent a hydrogen atom, a hydroxyradical, or an alkyl group in C₁-C₃₀, linear or ramified, saturated orunsaturated, possibly including one or several ethylenicunsaturation(s), and one or several substitute(s) chosen from among thegroup formed by the hydroxy radicals (OH), alkoxy radicals in C₁-C₆(OC₁-C₆) and carbonyl alkoxy in C₁-C₆ (COOC₁-C₆) radicals. 3.Composition according to claim 2, characterized in that the saidoxazoline is a type 1 oxazoline selected from the group composed of2-undecyl-4-hydroxymethyl-4-methyl-1,3-oxazoline,2-undecyl-4,4-dimethyl-1,3-oxazoline,(E)-4,4-dimethyl-2-heptadec-8-enyl-1,3-oxazoline,4-hydroxymethyl-4-methyl-2-heptadecyl-1,3-oxazoline,(E)-4-hydroxymethyl-1-4-methyl-2-heptadec-8-enyl-1,3-oxazoline, and2-undecyl-4-ethyl-4-hydroxymethyl-1,3-oxazoline.
 4. Compositionaccording to claim 3, characterized in that the said oxazoline is2-undecyl-4,4-dimethyl-1,3-oxazoline called OX-100 and its formula is:


5. Composition according to one of claims 1 to 4, characterized in thatit also comprises at least one inhibitor of metalloproteases (MMPs)advantageously selected from the group consisting of tissue inhibitorsof metalloproteinases, alpha-2-macroglobuline, plasminogen activatorinhibitors, zinc chelating agents, bryostatine-1, antibiotics, syntheticor natural peptides with a structure similar to the structure ofsubstrates of MMPs, retinoids, antioxidants, anti-cancer agents, malthydrolysates, extracts of marine algae, shark cartilage extracts andpeptide extracts of lupin.
 6. Composition according to claim 5,characterized in that the said inhibitor of MMPs is chosen from thegroup composed of peptide extracts of lupin, preferably extract B(LU105).
 7. Composition according to claim 5, characterized in that thesaid inhibitor of MMPs is chosen from the group composed of retinoids.8. Composition according to any one of claims 1 to 4, characterized inthat it also includes at least one compound chosen from the groupcomposed of PKC inhibitors, anti-inflammatory agents, soothing agents,immunosuppressors, ion chelating agents, alkanolamides, oxazolidinonesand derivatives of carbamic acid.
 9. Composition according to any one ofthe above claims, characterized in that the concentration in oxazolineis between approximately 0.001 and approximately 10% by weight, comparedwith the total weight of the composition.
 10. Composition according toany one of the above claims for its use as a medicine.
 11. Use of atleast one oxazoline as defined in any one of claims 1 to 4 or acomposition according to any one of claims 1 to 9 for preparation of amedicine intended to inhibit migration of dendritic cells, dermaldendrocytes, monocytes, lymphocytes, keratinocytes, mastocytes andendothelial cells.
 12. Use according to claim 11, characterized in thatthe medicine is intended to inhibit migration of Langerhans cells. 13.Use according to claim 11, characterized in that the medicine isintended for the treatment or prevention of allergic and/or inflammatoryand/or irritative reactions of the skin and/or mucosa.
 14. Use accordingto claim 11, characterized in that the medicine is intended for thetreatment or prevention of reactions or pathologies of the skin and/ormucosa, following migration of Langerhans cells induced by a dangersignal.
 15. Use according to claim 11, characterized in that themedicine is intended for the treatment or prevention of reactions orpathologies induced by chemical or metallic haptens.
 16. Use accordingto claim 11, characterized in that the medicine is intended for thetreatment or prevention of sensitive and/or reactive and/oruncomfortable and/or intolerant skin and/or mucosa, and/or skin and/ormucosa exhibiting a barrier disorder and/or exhibiting an immunologicimbalance related to intrinsic aging, extrinsic aging or hormonal aging.17. Use according to claim 11, characterized in that the medicine isintended for the treatment or prevention of atopic eczema and/or contacteczema, inflammatory dermatitis such as psoriasis, irritativedermatitis, auto-immune diseases, photo-immuno-suppression or graftrejection.
 18. Use according to claim 11, characterized in that themedicine is intended to reduce the allergizing and/or irritant nature ofa composition or a perfume.
 19. Cosmetic method for the treatment ofsensitive, irritated, intolerant or allergy-prone skin and/or mucosa, oraging skin and/or mucosa, to which a danger signal is applied,exhibiting a skin barrier disorder, with skin rashes or exhibitingnon-pathological immunologic imbalance, related to intrinsic aging,extrinsic aging or hormonal aging, characterized in that it consists ofapplying a composition according to claims 1 to 9 or at least one activecompound chosen from the oxazolines group as defined in any one ofclaims 1 to 4, to the skin and/or mucosa.